Epidemiologic studies have identified Factor V Leiden as the most common cause of heritable thrombophilia a prothrombotic mutation associated with a 5 to 7-fold increase in the risk of venous thromboembolism (VTE). In pre-menopausal women, the use of oral contraceptives is associated with a 4-fold increase in VTE risk, and the joint effects of oral contraceptive use and Factor V Leiden carriership increase the VTE risk of by a factor of 35 (95% IC = 8 154). Recently, the results of several observational studies and randomized clinical trials suggest that in post-menopausal women, the use of hormone replacement therapy is associated with a 3-fold increase in VTE risk. Whether post-menopausal women with prothrombotic mutations experience a similar 20-fold increase in risk when they take post-menopausal hormones remains unknown. The primary aim of this ancillary study is to assess the interaction between hormone replacement therapy and the prothrombotic mutations, Factor V Leiden and the recently described prothrombin mutation (20210A) on the incidence of VTE in a population-based case-control study conducted at Group Health Cooperative of Puget Sound (GHC). The investigators state that using a variety of computerized surveillance systems at GHC will enable them to identify both in-patient and out-patient episodes of venous thromboembolism. They anticipate recruiting 300 post-menopausal women with a first episode of objectively confirmed venous thromboembolism, and 1,200 population-based controls will be identified and recruited from the GHC enrollment files. Controls will be frequency matched to the cases on age and calendar-year. Data collection includes a review of ambulatory medical record and a telephone interview. The GHC computerized pharmacy database will be used to assess exposure to hormone replacement therapy. A venous blood specimen will be obtained from consenting subjects, processed into aliquots of white cells, plasma, and red cells, and stored at 70 degrees C prior to laboratory analysis. DNA will be extracted from white cells, and molecular genotyping assays will be conducted to assess carriership of prothrombotic mutations. Data from these various sources will be entered, linked and analyzed to address the specific aims. Under an additive model, the expected joint effects of HRT and carriership of prothrombotic mutations is 7. Compared with the null hypothesis for the additive model of a joint effect of 7, the investigators have 80% power to detect a difference between the alternative hypothesis of 18 and the null hypothesis of 7. If there is an important interaction between hormone replacement therapy and prothrombotic mutations, such a finding would offer important opportunities of VTE risk reduction by pre-treatment screening in the clinical setting for the prothrombotic mutations.